Newborn screening (NBS) programs currently screen more than 4 million U.S. infants per year. The intent of newborn screening is to detect potentially fatal or disabling conditions in newborns, thereby providing a window of opportunity for early treatment, often while the child is still asymptomatic. This public health program has saved countless lives through the identification of infants who are at risk for congenital disorders for which early interventions and treatments have the potential to reduce morbidity and mortality. In 2006 the American College of Medical Genetics and Genomics (ACMG) led the development of newborn screening guidelines that recommend that all newborn infants be screened for 29 core conditions and that 25 ?secondary conditions? identified during the core evaluations be reported. These recommendations have been accepted by the Department of Health and Human Services (HHS) Secretary's Advisory Committee on Heritable Disorders in Newborns and Children (ACHDNC) (originally authorized by the Children's Health Act of 2000), and the Secretary of HHS. There are now 34 core conditions and 26 secondary conditions that form the Recommended Uniform Screening Panel (RUSP). Most states now use this or very similar panels for newborn screening. There has been broad acceptance of these screening guidelines by state screening laboratories, and interest in adding new tests that have been appropriately vetted to the recommended panel. In addition, under the Newborn Screening Saves Lives Act of 2007 and reaffirmed under the Newborn Screening Saves Lives Reauthorization Act of 2014, the Hunter Kelly Newborn Screening Research Program within the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), part of the National Institutes of Health (NIH), is authorized to carry out, coordinate, and expand research in newborn screening. This is in keeping with the mission of NICHD, which is to ensure that every person is born healthy and wanted, that women suffer no harmful effects from reproductive processes, and that all children have the chance to achieve their full potential for healthy and productive lives. Specifically, the Intellectual and Developmental Disabilities (IDD) Branch within NICHD has as one of its research priorities to improve screening and early diagnosis for IDD conditions and develop early interventions and treatments for them. Hence, the Hunter Kelly Newborn Screening Research Program falls under the purview of the IDD Branch within NICHD/NIH. Currently, policies related to newborn screening are determined through analysis of the severity and incidence of each condition under consideration, the specificity and sensitivity of the screening test, the natural history of the disorder, and the efficacy, safety, and effectiveness of treatments available for the disorder. To date, there are thousands of rare disorders that have been identified and hundreds that could potentially benefit from newborn screening; however, research in this arena, where many of the disorders are rare diseases and states have varying rules and regulations related to newborn screening, has been challenging for investigators.